Positron emitting compounds may be employed as markers and imaging agents because their presence and location are indicated by the annihilation of a nearby electron and the consequent emission of two oppositely oriented gamma rays. Gamma ray detectors can be used to detect the event and precisely determine its location.
Positron Emission Tomography (PET) relies upon the use of positron emitting radiolabeled tracer molecules and computed tomography to examine metabolic processes or to detect targets within the living body of a patient or experimental animal. Once injected, the tracer is monitored with a positron camera or a tomograph detector array. This technology can be more sensitive than scanning techniques such as magnetic resonance imaging (MRI), ultrasound imaging, or X-ray imaging. Some of the major clinical applications for PET are oncology, neurology, and cardiology.
Tracer molecules used in PET imaging are generally prepared by replacement of a group or atom in an unlabeled tracer with a radioisotope containing group or atom or by joining the tracer to a radioisotope containing atom (e.g. by chelation). Some common positron-emitting radioisotopes commonly used are: fluorine-18 (18F); carbon-11 (11C); nitrogen-13 (13N); and oxygen-15 (15O). In addition, 64Cu has been appended to tracer molecules using copper chelation chemistry (Chen et al. Bioconjug. Chem. (2004) 15: 41-49).
18F is a particularly desirable radioisotope for PET imaging since it has a longer half-life than 11C, 13N and 15O, readily forms covalent bonds, and has a short range beta+ emission that provides for high resolution in PET imaging. 18F also does not suffer from a drawback associated with the use of 64Cu, whereby the copper may become sequestered by native proteins in a non-specific manner resulting in “streaking” of the PET image.
18F is not a naturally occurring isotope and is not found in fluorine or fluoride ions from natural sources. 18F is only produced in nuclear reactions, typically by bombardment of an appropriate target in a cyclotron or proton accelerator. 18F labeled tracer molecules are generally produced close to an accelerator facility. There are several facilities throughout the world that are able to produce 18F and labeled tracers are routinely supplied from these facilities.
PET tracers often are or include, a molecule of biological interest (a “biomolecule”). Biomolecules developed for use in PET have been numerous. They can be small molecules as ubiquitous as water, ammonia and glucose or more complex molecules intended for specific targeting in the patient, including labeled amino acids, nucleosides and receptor ligands. Specific examples include 18F labeled fluorodeoxyglucose, methionine, deoxythymidine, L-DOPA, raclopride and Flumazenil.
Several approaches for incorporating 18F in biomolecules are described in the following references: Kuhnast, B., et al. (2004) J. Am. Chem. Soc., 15, 617-627; Garg, P. K., et al. (1991) Bioconj. Chem., 2, 44-49; Lee, B. C., et al. (2004) J. Am. Chem. Soc., 15, 104-111; Chen, X., et al. (2004) J. Am. Chem. Soc., 15, 41-49; Glaser, M., et al. (2004) J. Am. Chem. Soc., 15, 1447-1453; Toyokuni et al. Bioconjug. Chem. (2003) 14: 1253-9; and Couturier, O., et al. (2004) Eur. J. of Nuc. Med. and Mol. Imaging, 31, 1182-1206). These processes involve replacement of an existing group on the biomolecule with 18F. These methods are time consuming, thereby reducing PET image resolution as a result of nuclear decay. Also the fluorination conditions can adversely affect a biomolecule.
Walsh et al. in J. Labelled Cpd. Radiopharm. 42, Suppl. 1(1999) and Journal of Nuclear Medicine, Supp. S. 2000, 41 1098 described PET precursor compounds containing one 18F, two phenyl groups and a tertiary-butyl group each bonded to a silicon atom. The two phenyl and tertiary-butyl groups were required to provide hydrolytic stability. One of the phenyl groups included a thio-reactive or amine-reactive group for subsequent bonding to a biomolecule.